The incidence of the homozygous genotype for hereditary hemochromatosis will be established in a typical Caucasian population by screening 10,000 presumably healthy blood donors. The screening probe will be the percent saturation of transferrin. Complete evaluation of body iron stores in individuals with an abnormal percent saturation of transferrin should establish that the homozygous genotype occurs in about 5 per 1,000. A long-term longitudinal study will be done on over 200 genotyped individuals who are heterozygous for the hemochromatosis allele. Periodic evaluation of body iron stores, including direct measurement of hepatic iron content in selected individuals, will either confirm the benignity of the heterozygous genotype or provide criteria for the selection of heterozygotes who require therapy. In order to determine if the hemochromatosis gene plays a role in the pathogenesis of porphyria cutanea tarda, approximately 100 individuals with familial and "sporadic" porphyria cutanea tarda will be studied. Pedigree studies in which individuals are genotyped both for porphyria (by the detection of a mutant uroporphyrinogen decarboxylase) and for hemochromatosis (by HLA typing and measurement of body iron stores) should establish that gene-gene interactions are responsible for the clinical expression of this form of porphyria. Finally, a series of in vitro experiments with macrophages and gastrointestinal mucosal cells from rats and humans will define the normal physiology and cellular iron uptake and release. Studies with cells from individuals with hereditary hemochromatosis will then be done. Comparisons of iron uptake and release by the normal and abnormal cells should identify the specific metabolic error that results in the mal-regulation of iron flow in hereditary hemochromatosis.